Some of the largest national labs have for a decade routinely used test kits that contain a preservative, BD SurePath, that is approved for Pap tests but not HPV testing. The labs continue to use the tests despite an FDA warning June 8 that HPV tests using SurePath can produce false negatives and national guidelines that call for using only FDA-approved tests, an Arizona Republic investigation has found.

The result: Women may be told they are free of HPV when, in fact, they aren't. Such a misdiagnosis can allow the virus or cancer to become established and more difficult to treat.

Both the FDA and the test's manufacturers have been aware of the false-negative problem for years.

During a woman's annual gynecological exam, most doctors take a single sample that labs can process for both Pap and HPV tests. But few gynecologists have been aware that their diagnoses may be based on potentially faulty HPV lab results.

"Those of us out here in the trenches have no idea; we just use whatever the lab gives us," said Kathleen Fry, a former Scottsdale, Ariz., gynecologist who moved to Colorado in October. Like almost every gynecologist interviewed, she was unaware of the issue with SurePath before being contacted by The Arizona Republic. She said she uses a competing product, ThinPrep, that is FDA-approved for both Pap and HPV tests.

More than 81 million American women were given Pap tests, HPV tests or both in the past three years, as part of their routine gynecological exams, according to surveys by the Centers for Disease Control and Prevention.

SurePath accounts for about a third of the HPV tests, or about 3 million a year, estimated Michael Farmer, a market analyst who specializes in the pathology and histology laboratory markets. Because no federal agency tracks HPV testing, hard data on SurePath's rate of false-negative HPV tests isn't publicly available. However, extrapolating from the findings of a Johns Hopkins University study suggests a thousand or more women tested each year using SurePath may be told they are HPV-free when they are not.

The National Cancer Institute estimates that of the more than 12,100 women in the United States who are diagnosed with cervical cancer each year, about 4,200 will die from it.

SurePath was submitted to the FDA for approval for HPV testing at least three times in the last 10 years, either by TriPath Imaging, the company that developed SurePath, or by Becton, Dickinson and Co., which acquired TriPath Imaging in 2007. TriPath conducted large-scale trials in 2002, 2004 and 2006 as part of its effort to gain FDA approval. Each time, the application was withdrawn.

Neither Becton, Dickinson, based in Franklin Lakes, N.J., nor the FDA would say why the applications were withdrawn. But it is not unusual, said Mark Stoler, a Virginia pathologist, editor-in-chief of Diagnostic Molecular Pathology and editor of the International Journal of Gynecologic Pathology, who said it often happens after it becomes apparent that the FDA is likely to deny an application.

Federal regulators and the companies have been aware of a false-negative issue for years, as they have gathered data for the FDA applications. The Arizona Republic could find no evidence that they had alerted labs, gynecologists or patients about this issue until last summer.

On June 8, Becton, Dickinson, in collaboration with the FDA, sent a bulletin to laboratory customers stating SurePath is not FDA-approved for use with the most common HPV test, hybrid-capture II. "Use of the SurePath sample may under certain conditions produce false-negative results ... (that) could lead to inappropriate patient management and potentially compromise patient safety," the bulletin stated.

Becton, Dickinson didn't reveal the rate of false-negative results in the bulletin or in response to questions. Because of gaps in federal law, when labs use medical products, such as SurePath, for non-FDA-approved purposes - which is permitted by law - there is little oversight to ensure those tests are providing accurate results.

New cervical-cancer screening guidelines issued in March 2012 by the U.S. Preventive Services Task Force may actually increase the risk that a false-negative HPV test poses because they recommend less-frequent screening, according to doctors involved in developing the guidelines. The new guidelines call for "co-testing" most women between 30 and 65 using both Pap and HPV tests, but only once every five years or alternatively screening with Pap alone every three years. Though the guidelines specifically recommend using only FDA-approved tests for HPV tests, laboratories continue to use SurePath for such tests.

Most leading national labs would not explain to The Republic why they use SurePath despite the warning. But each kit costs labs between $1 and $2 less than alternatives that are FDA-approved for HPV tests.

Becton, Dickinson executives referred questions to company spokeswoman Colleen White. She provided two written responses regarding HPV testing, stating that "because it is not an approved use, it is not appropriate for BD to discuss that use. In the U.S., we market and promote only the FDA-approved use of our SurePath test." That use is for Pap tests, which detect cancerous and pre-cancerous cells.

White wrote that "based on recent study results, a mutual decision was reached by BD and (the) FDA" to send out the bulletin. She noted that Becton, Dickinson's June bulletin recommended that when SurePath is used for Pap tests, doctors should collect a separate sample for HPV testing using an FDA-approved medium.

The victims

Pathologists interviewed described cases in which women who were tested using SurePath died of cervical cancer or had to undergo a radical hysterectomy after as many as three tests that failed to detect HPV over several years.

A recent cervical-cancer screening study by researchers at Johns Hopkins University School of Medicine, in Baltimore, included data on more than 17,000 women who were tested for HPV using the SurePath preservative. Out of the eight women in that group who turned out to have cancer, six had recorded at least one negative HPV test in the prior two and one-half years. The study's lead authors did not respond to email and phone inquiries about the findings.

Any test can produce false negatives. But given the warnings from the company and the FDA, labs that use SurePath for HPV testing "are potentially putting women at risk by increasing the likelihood of false negatives," said Phil Castle, a former investigator at the National Cancer Institute.

"Everybody's afraid to talk about these cases at their institutions," said Marshall Austin, director of cytopathology at Magee-Women's Hospital in Pittsburgh. "These cases are out there, but they aren't being noticed and systematically studied," Austin said.

A warning goes unheard

The bulletin may have not reached those who need the information for their patients. The letter went to laboratories - and only to laboratories. Gynecologists in 11 practices across the country, along with two national gynecological associations, said they were unaware of the bulletin five months after it was issued.

David Wilbur, director of clinical imaging at Massachusetts General Hospital, and professor of pathology at Harvard Medical School, said he doesn't see any reason for "unwarranted consternation" about SurePath's stability. However, Wilbur also said that "we stick to testing immediately because we're aware of this issue. ... I can't speak for what other laboratories do."